gamma-Lactone-functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I

To study the relevance of the terminal alpha,beta -unsaturated gamma -methy l-gamma -lactone moiety of the antitumoral acetogenins of Annonaceae for po tent mitochondrial complex I inhibition, we have prepared a series of semis ynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hyd roxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta -hydroxy gamma -methyl gamma -lactone acetogenins, laherradurin (3) a nd itrabin (4), are more potent complex I inhibitors than any other known c ompounds. (C) 2001 Elsevier Science Ltd. All rights reserved.